Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with more than 4.5 million Americans currently suffering from the disease. Clinical management of AD is complicated by lack of effective methods for early and accurate diagnosis of the disease. Thus, there is a significant unmet need for Alzheimer's disease diagnostic tools. The hypothesis of this project is that positron emission computed tomography (PET) imaging of pathological tau fibrils would provide an excellent biomarker for detection of tau pathology useful for both 1) Staging and monitoring progression of Alzheimer's disease and for 2) Improving early and accurate diagnosis of Alzheimer's and related tauopathies. To test this hypothesis, we will screen for and develop a novel 18F-labeled radiopharmaceutical to specifically and sensitively bind tau fibrils (the chief constituent of neurofibrillary tangles in Alzheimer's). Working with our collaborators, we have recently demonstrated a successful human proof of mechanism clinical trial for an amyloid plaque imaging agent. The tau imaging agent proposed here would provide a valuable complement to this amyloid agent by allowing for imaging of the two primary pathologies in Alzheimer's disease. Furthermore, the expertise we have developed on the amyloid project (which was also funded through SBIR grants) can now be directly applied to developing the tau specific agent. Thus Phase I of this project will now assess the feasibility of developing a tau agent by in vitro and mouse testing of multiple families of small molecules that we have developed. Phase II will test the characteristics of the biomarker proof of mechanism trials in patients under an exploratory IND. Successful accomplishment of these studies will yield an innovative radiopharmaceutical product for the evaluation and diagnosis of AD. A widely available imaging test for tau pathology in AD will yield significant scientific, commercial and societal benefits. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with more than 4.5 million Americans currently suffering from the disease. Clinical management of AD and related diseases (including fronto-temporal dementia) is complicated by lack of effective methods for early and accurate diagnosis and monitoring of disease progression. Successful accomplishment of this project will provide a tau specific molecular imaging agent. When used in conjunction with amyloid specific molecular imaging agents (such as the one Avid is already developing, supported by SBIR funding) the tau specific agent would represents a significant advance towards meeting these goals for accurate diagnosis and monitoring of AD and related diseases.